Academic Journal
OP0307 A NOVEL TARGETED APPROACH TO ACHIEVE IMMUNE SYSTEM RESET: CD45-TARGETED ANTIBODY DRUG CONJUGATES AMELIORATE DISEASE IN PRECLINICAL AUTOIMMUNE DISEASE MODELS AND ENABLE AUTO-HSCT
| العنوان: | OP0307 A NOVEL TARGETED APPROACH TO ACHIEVE IMMUNE SYSTEM RESET: CD45-TARGETED ANTIBODY DRUG CONJUGATES AMELIORATE DISEASE IN PRECLINICAL AUTOIMMUNE DISEASE MODELS AND ENABLE AUTO-HSCT |
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| المؤلفون: | Gillard, G., Proctor, J., Hyzy, S., Mikse, O., Lamothe, T., Mcdonough, S., Clark, N., Palchaudhuri, R., Bhat, A., Brooks, M., Sarma, G., Bhattarai, P., Sawant, P., Pearse, B., Mcdonagh, C., Boitano, T., Cooke, M. |
| المصدر: | Annals of the Rheumatic Diseases ; volume 79, issue Suppl 1, page 190-191 ; ISSN 0003-4967 1468-2060 |
| بيانات النشر: | BMJ |
| سنة النشر: | 2020 |
| الوصف: | Background: Resetting the immune system through autologous hematopoietic stem cell transplant (autoHSCT) is a highly effective treatment in selected patients with autoimmune diseases. AutoHSCT can induce long-term remission with 80% progression free survival in multiple sclerosis patients (Muraro 2017, Burt 2019). Use of autoHSCT in scleroderma patients has achieved superior outcomes in two randomized studies compared to standard of care (Tyndall 2014, Sullivan 2018). These impressive results are achieved by a combination of the eradication of autoreactive immune effector cells and re-establishment of self-tolerance, i.e., immune system reset. However, only a small fraction of eligible patients undergo autoHSCT, largely due to toxicity associated with current conditioning protocols. Objectives: As part of our goal to enable more patients to benefit from immune system reset, we have generated novel anti-human CD45 ADCs that cross react with nonhuman primates (NHP) and an anti-mouse CD45 ADC to model the approach in mouse models of AID. Methods: The human-targeted CD45-ADC is an affinity-matured mAb that targets an epitope present on all human CD45 isoforms, is cross-reactive with NHP CD45, and is conjugated to a payload that efficiently kills both quiescent and cycling cells. This ADC is engineered to eliminate Fc-mediated effector function, enable site-specific conjugation of linker/payload, and enable rapid clearance. This ADC was evaluated in vitro and in vivo in hNSG and NHPs. The murine tool ADC specifically targets the CD45.2 isoform of mouse CD45, and is also engineered to eliminate effector function, allow for site-specific conjugation of linker payload, and be rapidly cleared. The payload for this murine tool ADC is potent and preferentially kills dividing cells. This ADC was tested for the ability to enable immune reset and ameliorate autoimmune disease in multiple disease models. Results: The anti-human CD45-ADC showed efficient killing of human HSCs and human and cyno PBMC, including CD3 + cells from ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1136/annrheumdis-2020-eular.5744 |
| الاتاحة: | http://dx.doi.org/10.1136/annrheumdis-2020-eular.5744 https://syndication.highwire.org/content/doi/10.1136/annrheumdis-2020-eular.5744 |
| رقم الانضمام: | edsbas.7EDD73F6 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1136/annrheumdis-2020-eular.5744 |
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